Calcium functions as an intracellular mediator of a variety of physiological activities in cells. These activities include gene regulation, DNA synthesis, cell cycle regulation, signal transduction, release of neurotransmitters in the brain, and the breakdown of glycogen for muscle contraction. These effects are initiated when extracellular signals trigger the release of calcium either from the extracellular space or the endoplasmic reticulum into the cytosol. In the cytosol, calcium binds to a variety of calcium-binding proteins that further mediate the signal by activating other molecules leading to a particular physiological effect.
Calcium-binding proteins (CBP) are a super family of proteins related by the presence of a calcium-binding motif referred to as the "EF-hand" domain. This domain is characterized by a 12 amino acid loop flanked by two alpha-helices oriented at approximately 90.degree. to one another (Celio, M. R. et al. (1996) Guidebook to Calcium-binding Proteins, Oxford University Press, Oxford, UK, pp. 15-20). Most CBPs have multiple EF-hand motifs for binding calcium, and more than 250 such CBPs have been described.
Calmodulin (CaM) is the most widely distributed and the most common mediator of calcium effects. CaM contains four EF-hand domains and undergoes a conformational change when it binds calcium. Activation of CaM enables it to bind to other target proteins and alter their activity. Key targets of CaM are the CaM-dependent protein kinases that are involved in regulation of smooth muscle contraction, glycogen breakdown, and neurotransmission, and calcineuron that is involved in synaptic transmission in the brain.
Calcyphosine is another CBP that is regulated by both calcium binding and protein phosphorylation. Dog calcyphosine (p24) is a CBP which has three EF-hand domains and is phosphorylated by cyclic-AMP dependent protein kinase (Lefort, A. et al. (1989) EMBO 8:111-116). The exact function of p24 is unknown; however, its occurrence in various secretory tissues such as salivary glands, lung, and brain suggests that it may play a role in the regulation of ionic transport (Celio et al, supra). A similar calcium-binding phosphoprotein from rabbit, R2D5, is expressed predominantly in and may modulate signal transduction in olfactory neurons. R2D5 also has three EF-hand domains and is phosphorylated by both cAMP-dependent protein kinase and CaM-kinase (Nemoto Y. et al. (1993) J. Cell Biol. 123:963-76).
The regulation of CBPs has implications for the control of a variety of disease conditions. The immunosuppressive agents cyclosporin and FK506 appear to act in part by inhibiting calcineuron mediated T-cell activation. Such inhibition indicates the importance of calcineuron, and hence CaM, in the immune response (Schwaninger M. et al. (1993) J. Biol Chem. 268:23111-15). Calcineuron also appears to be important for synaptic transmission in the brain and may be involved in learning and memory disorders (Mulkey R. M. et al. (1993) Science 261:1051-55). Since CaM-kinases are involved in muscle contraction and neurotransmission, they may play a role in muscular and neurological disorders.
The discovery of a new calcium-binding phosphoprotein and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention, and treatment of neurological and developmental disorders.